Staphylococcus aureus is a Gram-positive spherical bacterium. Annual US mortality exceeds that of any other infectious disease, including HIV/AIDS, and S. aureus is the leading cause of bloodstream, lower respiratory tract, skin & soft tissue infections. It is also the predominant cause of bone infections worldwide, and these infections are painful, debilitating and difficult to treat.
Treatment of S. aureus is becoming increasingly challenging due to the development of antibiotic resistance by many strains of S. aureus. Methicillin-resistant S. aureus (MRSA) is found in over half of all community and hospital infections. Recent years have seen the emergence of MRSA strains which are also resistant to vancomycin, the antibiotic of last resort, and which are essentially untreatable.
There is currently no authorised vaccine. A vaccine based on a mixture of surface polysaccharides from bacterial types 5 and 8, StaphVAX™, failed to reduce infections when compared to the placebo group in a phase III clinical trial. Similarly, the V710 vaccine [1], based on the IsdB antigen [2], failed to reduce the rate of post-operative S. aureus infections [3].
The need for a vaccine is particularly acute due to problem of antibiotic resistance and the fact that S. aureus infection does not provide immunity from future infection thanks to its well-developed immune evasion capabilities. The immune evasion properties of S. aureus in turn render the development of effective vaccines more difficult. The mechanisms of immune evasion are not fully understood, but are at least in part due to staphylococcal protein A (SpA), an S. aureus surface molecule that binds to Fc of immunoglobulin (Ig) and to the Fab portion of VH3-type B cell receptors. Interaction of SpA with B cell receptors leads to clonal explansion and subsequent cell death of B cell populations, leading to ablation of the adaptive immune response. SpA binding to Ig Fc interferes with opsonophagocytic clearance of staphylococci by polymorphonuclear leukocytes.
Mutant forms of SpA with reduced affinity to immunoglobulins have been developed. WO2011/005341 describes a SpA with point mutations in each of the five Ig-binding domains which reduce the ability of the protein to bind to IgG.
Reference 4 discloses various approaches to providing improved S. aureus vaccines, including two preferred immunogen combinations referred to as “Combo-1” and “Combo-2”. “Combo-1” included five antigens EsxA, EsxB, a mutant Hla, FhuD2, and Sta011, whereas “Combo-2” used a fragment of IsdA in place of the mutant Hla. Both of these combinations were tested with aluminium hydroxide adjuvants and they increased median survival time in a mouse model of infection when compared to buffer alone or to the IsdB antigen. “Combo-1” has also been tested with an aluminium hydroxide adjuvant and a TLR7 agonist, and the addition of the TLR7 agonist improved responses [5].
Despite the positive results with “Combo-1” and “Combo-2”, there remains a need for further and improved compositions for immunising against S. aureus. 